Skeletal muscle nuclei are permanently post-mitotic and thus incapable of self-renewal. A specialized cell type, located beneath the basement membrane of the muscle fiber, commonly known as the satellite cell, is responsible for maintenance and repair of muscle tissue. These cells are maintained in a quiescent state, but once activated, will proliferate extensively to form a pool of myoblasts that will differentiate and regenerate or repair muscle tissue. Loss of skeletal muscle tissue regenerative capacity is generally acknowledged to be the underlying deficit in severe examples of muscle wasting such as Duchenne Muscular Dystrophy, aging, and immunodeficiencies where cachexia is of clinical significance. If the mechanisms underlying the regulation of satellite cell quiescence and activation were better understood muscle regeneration could be manipulated. Such knowledge is expected to provide important new information for designing cell-based therapies to treatment of muscle tissue loss. Presently, little is known regarding the mechanisms that either maintain quiescence in satellite cells or signal their activation. We propose that these signals must be integrated such that the coordination of muscle regeneration occurs with the correct temporal sequence. We have identified an intracellular signal responsible for satellite cell activation. Active or dually pbosphorylated p38 alpha/beta MAPK (p38alpha/Beta-PO4) is required for satellite cell activation, allowing cells to respond to signals for proliferation or for differentiation. We hypothesize that p38alpha/Beta regulates these events as a primary "molecular switch" for satellite cell activation. Inhibition of p38alpha/Beta maintains satellite cells in a reversible quiescent state during which the cells are not responsive to growth factors. We propose to test the hypothesis that p38a/B functions as a primary regulator of the satellite cell quiescent state. Our specific aims are to: (1) Characterize the role of p38alpha/Beta-PO4 in satellite cell activation. We propose that p38a/B is essential for satellite cell activation. We will test this hypothesis by correlating the presence and subcellular localization of p38alpha/Beta-PO4 in normal regenerating muscle, in mdx muscles where p38-alpha/Beta is expected to be hyperactivated, and in syndecan-4 -/- muscles where satellite cell activation is impaired, (2) Identify signaling pathways that regulate p38a/B-PO4 activity. We propose that FGFR signaling is required for either the initial activation and/or maintenance of active p38a/B in satellite cells. We will test this hypothesis by inhibiting FGF signaling from both FGFRs known to be expressed on quiescent satellite cells and by assessing the ability of satellite cells to activate. We further propose that MKP-1 functions as a primary negative regulator of p38alpha/Beta activity. We will test this hypothesis by examining of p38alpha/Beta activation and localization in satellite cells from MKP-1 -/-mice, and (3) Identify and characterize p38alpha/Beta interacting proteins and cellular targets. We propose that p38a/B interacting proteins form complexes responsible for both regulation of p38alpha/Beta activity and for transduction of signals from phosphorylated p38a/B. We will test this hypothesis by identifying and isolating p38alpha/Beta-PO4 interacting partners and elucidate the cellular function of these interacting partners.